EP0117345B1 - Aminopyrimidinone als Histamin-H2-Antagonisten - Google Patents

Aminopyrimidinone als Histamin-H2-Antagonisten Download PDF

Info

Publication number
EP0117345B1
EP0117345B1 EP83307257A EP83307257A EP0117345B1 EP 0117345 B1 EP0117345 B1 EP 0117345B1 EP 83307257 A EP83307257 A EP 83307257A EP 83307257 A EP83307257 A EP 83307257A EP 0117345 B1 EP0117345 B1 EP 0117345B1
Authority
EP
European Patent Office
Prior art keywords
alkyl
formula
oxopyridin
pyrimidin
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP83307257A
Other languages
English (en)
French (fr)
Other versions
EP0117345A3 (en
EP0117345A2 (de
Inventor
Thomas Henry Brown
Derek Anthony Rawlings
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Smith Kline and French Laboratories Ltd
Original Assignee
Smith Kline and French Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smith Kline and French Laboratories Ltd filed Critical Smith Kline and French Laboratories Ltd
Priority to AT83307257T priority Critical patent/ATE50574T1/de
Publication of EP0117345A2 publication Critical patent/EP0117345A2/de
Publication of EP0117345A3 publication Critical patent/EP0117345A3/en
Application granted granted Critical
Publication of EP0117345B1 publication Critical patent/EP0117345B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to pyrimidinone derivatives, processes for their preparation, pharmaceutical compositions containing them and their use as histamine antagonists.
  • Histamine a physiologically active compound endogenous in mammals, exerts its action by interacting with certain sites called receptors.
  • receptors One type of receptor is known as a histamine H 1 -receptor (Ash and Schild, Brit. J. Pharmac. Chemother. 27427 (1966)) and the actions of histamine mediated through these receptors are blocked by drugs commonly called “antihistamines" (histamine H 1 -antagonists) a common example of which is mepyramine.
  • a second type of histamine receptor is known as the H 2 - receptor (Black et al. Nature 1972, 236, 385). These receptors are not blocked by mepyramine but are blocked by burimamide. Compounds which block these histamine H 2 -receptors are called histamine H 2 - antagonists.
  • Histamine H 2 -antagonists are useful in treating disease conditions caused by the biological effects of histamine mediated through H 2 -receptors, for example, as inhibitors of gastric acid secretion, in the treatment of inflammation mediated through histamine H 2 -receptors and as agents which act on the cardiovascular system, for example, as inhibitors of effects of histamine on blood pressure mediated through histamine H 2 -receptors.
  • Cimetidine is an example of a histamine H 2 -antagonist. Cimetidine has been shown to be useful in the treatment of duodenal, gastric, recurrent and stomal ulceration, and reflux oesophagitis and in the management of patients who are at high risk from haemorrhage of the upper gastrointestinal tract.
  • the compounds of the formulae (A) and (B) are also reported to have histamine H i -antagonist activity.
  • histamine H i - and H 2 -receptors In some physiological conditions the biological actions of histamine are mediated through both histamine H i - and H 2 -receptors and blockade of both types of receptors is useful. These conditions include inflammation mediated by histamine, for example skin inflammation, and those hypersensitivity responses due to the action of histamine at H i - and H 2 -receptors, for example allergies.
  • the present invention provides a compound of the formula (I):- and pharmaceutically acceptable salts thereof, wherein
  • 2-pyridyl optionally substituted by one or more C 1-6 alkyl, C 1-6 alkoxy, halo, amino or hydroxy moieties or substituted in the 4 - position by a group R 3 R 4 N(CH 2 ) m ⁇ wherein R 3 and R 4 are independently hydrogen, C 1-6 alkyl, phenyl(C 1-6 )alkyl, thienyl(C 1-6 )alkyl, furyl(C 1-6 )alkyl, hydroxy(C 1-6 )alkyl, halo(C 1-6 )alkyl or C 3-8 cycloalkyl; or together with the nitrogen atom to which they are attached form a 5-8 membered saturated ring; and m is 1 to 6;
  • R 5 and R 6 are independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, halo(C 1-6 )alkyl, C 3-6 alkenyl, phenyl(C 1-6 )alkyl, C 3-6 alkynyl, hydroxy(C 1-6 )alkyl, C 1-3 alkoxy(C 1-6 )alkyl, trifluoro(C 1-6 )alkyl, amino(C 1-6 )alkyl, C 1-3 alkylamino(C 1-6 )alkyl or di-(C 1-3 )alkylamino(C 1-6 )alkyl; or R 5 and R 6 together with the nitrogen atom to which they are attached form a 5-8 membered saturated ring;
  • phenyl optionally substituted by C 1-6 alkyl, C 1 - s alkoxy, hydroxy, halo, trifluoromethyl, nitro, amino, C 1-6 alkylamino, C 1-6 alkanoylamino, di(C 1-6 )alkylamino or cyano and further optionally substituted in any one of the 3-, 4-, or 5-positions by ⁇ (CH 2 mNR 5 R 6 , ⁇ OCH 2 CH 2 NR 5 R 6 or ⁇ OCH 2 CH 2 CH 2 NR 5 R 6 ;
  • A is C 1-5 methylene or ⁇ (CH 2 ) p W(CH 2 ) q where W is oxygen or sulphur and p and q are such that their sum is from 1 to 4;
  • R 2 is a pyridone moiety substituted on the nitrogen atom by a group R 7 wherein R 7 is ⁇ (CH 2 ) r NR 8 R 9 wherein R S and R 9 are independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-6 alkenyl, phenyl(C 1-6 )alkyl, C 3-6 alkynyl, hydroxy(C 1-6 )alkyl, C 1-3 alkoxy(C 1-6 )alkyl, trifluoro(C 1-6 )alkyl, amino(C 1-6 )alkyl, C 1-3 alkylamino(C 1-6 )alkyl or di-(C 1-3 )alkylamino(C 1-6 )alkyl; or R S and R 9 together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino or hexahydroazepino ring, and r is 2 to 6; or R 7 is
  • R 7 is C 1 - 4 alkyl optionally substituted by hydroxy, C 1 - 4 alkoxy or phenyl
  • Z is hydrogen
  • R' is not 2-pyridyl disubstituted, in the 3-position by halo, amino, C 1-4 alkyl or C 3 - 4 alkoxy and in the 5-position by halo, amino or C 1-4 alkyl.
  • alkyl and alkoxy mean groups which can be straight or branched.
  • preferred alkyl groups are methyl, ethyl, prop-1-yl and prop-2-yl.
  • alkoxy groups are methoxy, ethoxy, prop-1-oxy and prop-2-oxy.
  • R 1 is 2- or 4-imidazolyl optionally substituted by C 1-6 alkyl, halo, trifluoromethyl or hydroxymethyl; 2-thiazolyl; 2-guanidino-4-thiazolyl optionally substituted by chloro, bromo or C 1-6 alkyl; 2-(5-amino-1,3,4-thiadiazolyl); 3-isothiazolyl optionally substituted by chloro or bromo; 3-(1,2,5)-thiadiazolyl optionally substituted by chloro or bromo; 2-pyridyl optionally substituted by one or more C 1-6 alkyl, C 1-6 alkoxy, halo, amino or hydroxy moieties or substituted in the 4-position by a group R 10 R 11 NCH 2 ⁇ wherein R 10 and R" are independently hydrogen or C 1-6 alkyl, or together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino ring; 2-furyl or 2-
  • R 1 is 2- or 4-imidazolyl substituted by methyl, bromo or chloro.
  • R' is 2-guanidino-4-thiazolyl.
  • R 1 is 2-pyridyl substituted by methyl, ethyl, hydroxy, methoxy, ethoxy, chloro, bromo or iodo. Preferably such substituents are in the 3-position, for example 3-bromo and 3-hydroxy.
  • R 1 may be 2-pyridyl substituted in the 4-position by a group R 3 R 4 N(CH 2 ) m wherein R 3 , R 4 and m are as hereinbefore defined.
  • m is one.
  • R 3 and R 4 are independently hydrogen or C 1-6 alkyl or together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino ring.
  • R 1 is 2-pyridyl substituted in the 4-position by dimethylaminomethyl, pyrrolidinomethyl or piperidinomethyl.
  • R 1 is 2-furanyl or 2-thienyl substituted in the 5-position by a group R 5 R 6 NCH 2 ⁇ wherein R 5 and R 6 are as hereinbefore defined.
  • R 5 and R 6 are independently selected from C 1-6 alkyl, trifluoroC 1-6 alkyl for example trifluoroethyl, or R 5 and R 6 together with the nitrogen atom to which they are attached form a piperidino or pyrrolidino ring.
  • R 5 is methyl or ethyl.
  • R 6 is hydrogen, methyl or ethyl.
  • R 5 R 6 NCH 2 ⁇ represents dimethylaminomethyl.
  • R 5 N 6 CH 2 ⁇ represents piperidinomethyl.
  • R 1 is phenyl either unsubstituted in the 2-position or substituted in that position by C 1-6 alkyl for example methyl, C 1-6 alkoxy for example methoxy, hydroxy, halo such as chloro, trifluoromethyl, amino or cyano.
  • the phenyl ring is substituted in the 2-position by methoxy or chloro when there are no further substituents.
  • the phenyl ring is unsubstituted in the 2-position when there is a substituent at the 3-, 4- or 5-position.
  • such a substituent is a group R 5 R 6 NCH 2 ⁇ wherein R 5 and R S are as hereinbefore defined.
  • R 5 is C 1-6 alkyl for example methyl or ethyl, or is trifluoroethyl
  • R 6 is hydrogen or C 1-6 alkyl for example methyl or ethyl.
  • R 5 R 6 NCH 2 ⁇ represents dimethylaminomethyl.
  • R S R 6 NCH 2 - represents piperidinomethyl.
  • X is methylene.
  • X is oxygen when R 1 is phenyl substituted by a group R 5 R 6 N(CH 2 ) m ⁇ or pyridyl substituted by a group R 5 R 6 N(CH 2 ) m .
  • Y is sulphur
  • R' is of the sub-formula (i): wherein R 14 and R 15 are independently C 1-6 alkyl or together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino ring; R 16 is 4-pyrid-2-yl, 5-furan-2-yl or 1,3-phenylene.
  • R 14 and R 15 are both methyl or together with the nitrogen atom to which they are attached form a piperidino ring.
  • R 16 is 5-furan-2-yi or 1,3-phenylene, preferably 5-furan-2-yl.
  • R'-X-Y- represents include: 3-methoxypyrid-2-ylethyl, 5-methyl-4-imidazolylmethylthio, and 2-guanidino-4-thiazolylmethylthio, and in particular:
  • A is straight or branched alkylene, preferably straight and in particular methylene.
  • A is -(CH 2 )pW(CH 2 )q wherein W is oxygen, p is zero and q is one (i.e. ⁇ OCH 2 ⁇ ).
  • Other examples of A include methoxymethyl, methylthiomethyl, methoxyethyl and methylthioethyl.
  • R 2 is a pyridone ring substituted on the nitrogen by R 7 and may exist in any of the isomeric forms (a)-(f):- 6-oxopyridin-3-yl 2-oxopyridin-3-yl 4-oxopyridin-3-yl 2-oxopyridin-4-yl 6-oxopyridin-2-yl 4-oxopyridin-2-yl
  • R 7 is a group R 8 R 9 N(CH 2 ) r ⁇ wherein r, R" and R 9 are as hereinbefore defined. More suitably R 8 is C 1-6 alkyl for example methyl or ethyl, or is trifluoroethyl, and R 9 is hydrogen or C 1 - s alkyl for example methyl or ethyl.
  • R 8 R 9 N ⁇ represents piperidino or pyrrolidino.
  • r is 2.
  • R 7 is dimethylaminoethyl, piperidinoethyl or N-(2,2,2)-trifluoroethyl-N-methyl aminoethyl.
  • R 7 is phenyl(C 1 - 6 )alkyl for example benzyl, or phenethyl, or R 7 is C 1-6 alkyl for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or n-pentyl.
  • R 7 Particularly favoured values of R 7 are methyl, ethyl, n-butyl, benzyl or dimethylaminoethyl.
  • the activity of the compounds of formula (I) as histamine H 2 -antagonists can be demonstrated by their ability to inhibit histamine-stimulated secretion of gastric acid from the lumen-perfused stomachs of rats anaesthetised with urethane, and to reverse histamine-induced inhibition of contractions of the isolated rat uterus. These are actions of histamine which, according to Ash and Schild, Brit. J. Pharmac. Chemother. 27 247 (1966), are not mediated by histamine H I -receptors.
  • histamine H 2 -antagonist activity of the compounds can also be demonstrated by the inhibition of histamine-stimulated acid secretion in the Heidenhain Pouch Dog, the inhibition of histamine-induced tachycardia in the isolated guinea pig right atrium and the inhibition of histamine-induced vasodilatation in the anaesthetised cat.
  • the compound of Example 2 has an unexpected advantageous effect over analogous compounds of the art, for example Example 7 of EP-A-3677, in that it is more effective after intraduodenal administration to anaesthetised rats.
  • the inhibition of histamine-stimulated secretion of gastric acid in rats anaesthetised with urethane was measured after administration of test compounds by intraduodenal injection and intravenous injection.
  • the intraduodenal dose required to produce 50% inhibition was only 3 times the intravenous dose required to produce a similar effect
  • the intraduodenal dose required was 10 times the intravenous dose.
  • the compound of Example 7 of EP-A-3677 required an intraduodenal dose 500 times that of the intravenous dose required to inhibit acid secretion by 50%. Good activity after intraduodenal injection is indicative that there will good activity after oral administration.
  • the invention further provides pharmaceutical compositions comprising a compound of formula (I) above or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.
  • Compounds of formula (I) and their pharmaceutically acceptable salts may be administered orally, parenterally, cutaneously or rectally.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a suitable liquid carrier for example, ethanol, glycerine or water with a flavouring or colouring agent.
  • a suitable liquid carrier for example, ethanol, glycerine or water with a flavouring or colouring agent.
  • any suitable pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.
  • Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous carrier or parenterally acceptable oil.
  • compositions for administration to the skin include lotions and creams in which the compound of formula (I) or salt thereof is contained in a liquid vehicle.
  • a typical suppository formulation comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent such as gelatin or cocoa butter or other low melting vegetable waxes or fats.
  • the composition is in unit dose form such as a tablet or capsule so that the patient may administer to himself a single dose.
  • compositions of the invention will normally be administered to man for the treatment of peptic ulcers and other conditions caused or exacerbated by gastric acidity in the same general manner as that employed for known histamine H 2 -antagonists, due allowance being made in terms of dose levels for the potency of the compound of the present invention relative to known histamine H 2 - antagonists.
  • an adult patient will receive an oral dose of between 15 mg and 1500 mg and preferably between 20 mg and 250 mg or an intravenous, subcutaneous, or intramuscular dose of between 1.5 mg and 150 mg, and preferably between 5 mg and 20 mg of compound of formula (I) or pharmaceutically acceptable salt thereof calculated as the free base, the composition being administered 1 to 6 times per day.
  • This invention further provides a process for preparing a compound of the formula (I) or a pharmaceutically acceptable salt thereof which process comprises:
  • Q is nitroamino, C 1-6 alkylthio, benzylthio, chloro or bromo. Of these nitroamino is preferred.
  • This process can be performed in the absence of solvent at an elevated temperature, or in the presence of a substantially inert polar solvent for example pyridine, anisole or C 1-6 alkanol at an ambient or elevated temperature.
  • a substantially inert polar solvent for example pyridine, anisole or C 1-6 alkanol at an ambient or elevated temperature.
  • Q is nitroamino
  • the reaction may be carried out in a C 1 - 6 alkanol, for example ethanol or isopropanol, pyridine or anisole at the reflux temperature of the reaction mixture.
  • Q is methylthio the reaction may be performed in the absence of solvent at 140°-170°, or the reaction may be performed in refluxing pyridine or anisole.
  • examples of the moiety L include chloro, bromo, hydroxy, C 1-6 alkoxy for example methoxy, C 1-6 alkanoyloxy for example acetoxy, arylsulphonyloxy for example 4-methylbenzenesulphonyloxy or C 1-6 alkylsulphonyloxy for example methanesulphonyloxy.
  • L is hydroxy in which case the reaction is performed under acidic conditions.
  • L is chloro or bromo it is preferable to perform the reaction in the presence of a strong base for example sodium ethoxide in ethanol.
  • L is an arylsulphonyloxy or alkylsulphonyloxy group the reaction is preferably performed under mildly basic conditions for example in pyridine solution.
  • the reaction between the compounds of the formulae (VI) and (VII) is suitably carried out in the presence of a base.
  • suitable bases include alkali metal hydroxides and C 1-4 alkoxides, sodium hydride, and quaternary ammonium hydroxides for example benzyltrimethylammonium hydroxide.
  • the base is sodium ethoxide or sodium methoxide.
  • the reaction can be carried out in the presence of a solvent the choice of which is not critical to the success of the process provided that it is substantially inert to the reagents and product.
  • the solvent is a C 1-4 alkanol, (for example, methanol, ethanol or propanol) or dimethylformamide.
  • the reaction can be carried out at moderate temperatures, for example from room temperature to the reflux temperature of the solvent.
  • R 17 is methyl or ethyl.
  • s and t are both zero so that the group R3R4NCO- (or R 5 R 6 NCO-) is a precursor to the group R 3 R 4 NCH 2 - (or R 5 R 6 NCH 2 ⁇ ).
  • the reduction of such a group R 3 R 4 N(CH 2 ) s CO(CH 2 ) t ⁇ may be performed with a hydride for example lithium aluminium hydride.
  • R' 8 has a substituent CHO ⁇ (CH 2 ) m-1 ⁇ , which may be converted to a group R 3 R 4 N(CH 2 ) m ⁇ (or R 5 R 6 N(CH 2 ) m ⁇ ) on reaction with an amine under conditions of reductive amination.
  • R 18 may have a substituent HO(CH 2 ) m ⁇ which may be converted, for example via Cl(CH 2 ) m ⁇ , to R 3 R 4 N(CH 2 ) m ⁇ (or R 5 R 6 N(CH 2 ) m ⁇ ). Such transformations may be carried out in conventional manner.
  • compounds of the formula (I) wherein R 1 is furyl or thienyl either substituted by a R 5 R 6 NCH 2 ⁇ group may be prepared from the corresponding compounds of formula (I) wherein R' is substituted by hydrogen at the relevant position, by reaction with a Mannich reagent, for example formaldehyde and an amine R 5 R 6 NH or salt thereof.
  • a Mannich reagent for example formaldehyde and an amine R 5 R 6 NH or salt thereof.
  • This reaction may be carried out by treatment of an amine salt with aqueous formaldehyde and a compound of the formula (I) (wherein R' is substituted by hydrogen at the relevant position), or by refluxing an amine salt with paraformaldehyde and a compound of the formula (I) (wherein R' is substituted by hydrogen at the relevant position) in a convenient solvent such as ethanol.
  • the Mannich reagent may be a di-(C 1 - 4 alkyl)methylene ammonium salt for example dimethylmethylene ammonium chloride or iodide, or may be a bis di-C 1-4 alkylamino methane, for example bis(dimethylamino)methane.
  • Any group in the remainder of the molecule that is capable of reacting with a Mannich reagent may be optionally protected during the reaction, and may be subsequently deprotected in conventional manner.
  • the compounds of the formula (IX) may be reduced to form compounds of the formula (1) for example using hydrides.
  • Q' is chloro or bromo.
  • the reaction is performed under basic conditions, for example the anion of the compound of the formula (X) may be generated, for example using sodium hydride.
  • the reaction is performed in a suitable aprotic solvent for example dimethylformamide at a non-extreme temperature for example between 0°C and 100°C, suitably between ambient and 70°C.
  • Q 2 is chloro, bromo, arylsulphonyloxy for example 4-methylbenzenesulphonyloxy or C 1 - 6 alkylsulphonyloxy for example methanesulphonyloxy.
  • arylsulphonyloxy for example 4-methylbenzenesulphonyloxy or C 1 - 6 alkylsulphonyloxy for example methanesulphonyloxy.
  • Such reactions are generally performed in the presence of a base for example triethylamine, an alkoxide or a hydroxide.
  • Pharmaceutically acceptable acid addition salts of the compounds of the formula (I) may be prepared from the corresponding base of the compounds of the formula (I) in conventional manner.
  • the base may be reacted with an acid in a C 1-4 alkanol, or an ion-exchange resin may be used.
  • the salts of the compounds of the formula (I) may be interconverted using ion-exchange resins.
  • Non-pharmaceutically acceptable salts are therefore of use as they can be converted to pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of the formula (I) include those formed with hydrochloride, hydrobromic, sulphuric, phosphoric, acetic, citric, maleic, lactic, ascorbic, fumaric, oxalic, methanesulphonic and ethanesulphonic acids.
  • the compounds of the formulae (II), (IV) and (XII) are preparable by the methods described in EPA-3677, 4793,13071, 15138, 17679, 17680 and 49173 and GB ⁇ A ⁇ 2030979.
  • the compounds of the formula (III) wherein Q is nitroamino may be prepared by the reaction of a compound of the formula (VII) with nitroguanidine.
  • the compound of the formula (III) wherein Q is C 1-6 alkylthio or benzylthio may be prepared by the reaction of a compound of the formula (VII) with thiourea followed by alkylation or benzylation.
  • the compounds of the formula (VIII) may be prepared in a manner analogous to that described for the preparation of compounds of the formula (I), for example reacting a compound of the formula (III) with an analogue of a compound of the formula (II) wherein R 1 is replaced by R 18 ; provided that R' 8 is suitably protected as necessary.
  • the compounds of the formula (IX) wherein R 19 is ⁇ CONH ⁇ may be prepared by the reaction of a compound of the formula (XV) with an activated derivative of a compound of the formula (XVI): wherein R 1 , X and Y are as hereinbefore defined.
  • Suitable active derivatives are acyl halides, anhydrides and activated esters.
  • the aldehydes of the formula (XIV) may be prepared for example by reacting a compound of the formula (XVII): wherein R 1 is as hereinbefore defined, with a protected bromopropionaldehyde (for example protected as a cyclic acetal) and deprotecting.
  • the acid of the formula (XVI) and derivatives thereof may be prepared in similar manner for example by reacting a compound of the formula (XVII) with a protected bromopropionic acid and if necessary deprotecting and/or converting to the desired activated acid derivative.
  • the compounds of the formulae (V), (XI) and (XIII) may be prepared for example by methods analogous to that described for the reaction of compounds of the formulae (II) and (III), that is reacting a compound of the formula (III) with HSCH 2 CH 2 NH 2 , Q 1 CH 2 CH 2 CH 2 NH 2 , or Q 2 CH 2 CH 2 NH 2 , wherein the nature of the groups Q 1 and Q 2 is such that the desired reaction occurs.
  • the compounds of the formula (VII) wherein Z is hydrogen may be prepared for example by the reaction of a compound of the formula (XVIII):- wherein A, R 2 and R 17 are as hereinbefore defined, with a formylating agent, for example a C 1-6 alkyl formate such as ethyl formate, in the presence of a strong base.
  • a formylating agent for example a C 1-6 alkyl formate such as ethyl formate
  • sodium hydride in 1,2-dimethoxyethane or tetrahydrofuran may be used.
  • sodium in ether may be used.
  • the compounds of the formula (VII) wherein Z is hydrogen or C 1 - 6 alkyl may be prepared in conventional manner, such as adaptation of the disclosure of British Specification 1582527.
  • the compounds of the formula (VI) may be prepared by the reaction of a compound of the formula (II) with a compound of the formula (XIX):- wherein T is a leaving group such as methylthio.
  • any groups may be optionally protected, if appropriate, in conventional manner.
  • suitable amino-protecting groups for the processes described herein include tertiarybutyloxycarbonyl removable by trifluoroacetic acid, benzyloxycarbonyl removable by hydrogenolysis or hydrobromic acid, and phthaloyl removable by hydrazine.
  • Suitable hydroxy protecting groups include benzyloxycarbonyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, benzyl, C 1-6 alkyl for example methyl, and acyl for example formyl or acetyl.
  • N-Methyl-4-formyl-2-pyridone * (30.17 g), monoethyl malonate (38.15 g), pyridine (150 ml) and piperidine (3 ml) were stirred under reflux for 6) hours.
  • the reaction mixture was evaporated under reduced pressure to afford a residue which was crystallised from aqueous isopropanol to give ethyl ⁇ -(N-methyl-2-oxo-4-pyridyl)acrylate as a pale yellow solid (18.44 g), m.p. 126-7°C.
  • a solution of sodium (2.31 g) in methanol (50 ml) was prepared. To this was added, with stirring, nitroguanidine (9.28 g) (containing 25% w/w water) and methanol (10 mI). The mixture was stirred under reflux for one hour and a semi-solution, semi-suspension of ethyl a-formyl-p-(N-methyl-2-oxo-4-pyridyl)propionate (15.87 g) in methanol (60 ml) was added over the period of one hour. The reaction mixture was refluxed for 20 hours, and evaporated under reduced pressure to afford an oil.
  • N-n-Butyl-4-(ethylenedioxymethyl)-2-pyridone (94.49 g) and 3% hydrochloric acid (50 ml of concentrated hydrochloric acid made up to 570 ml) were heated on a steam bath for 30 minutes. The solution was allowed to cool overnight and taken to pH 8 with potassium carbonate solution. The reaction mixture was extracted into chloroform (6 x 200 ml), and the combined chloroform extracts were washed with water (2 x 50 ml), dried over MgS0 4 and evaporated under reduced pressure to afford an oil. This oil was washed with petroleum ether (40°-60°) and on cooling N-n-butyl-4-formyl-2-pyridone was obtained as a solid (64.37 g), m.p. 36-40°C.
  • N-n-Butyl-4-formyl-2-pyridone (68.71 g), malonic acid (39.90 g), pyridine (225 ml) and piperidine (4.5 ml) were stirred under reflux for 6 hours.
  • the reaction mixture was evaporated under reduced pressure to afford an oil, to which was added water and a small amount of ammonia ('880 solution) to aid dissolution.
  • the solution was taken to pH 4 with acetic acid, the solvent volume was diminished under reduced pressure and acetone added to precipitate a solid.
  • a pharmaceutical composition for oral administration is prepared by mixing together the product of Example 2 (55% wt/wt), dibasic calcium phosphate dihydrate (20%) and colouring agent (0.5%), adding a concentrated solution of polyvinylpyrrolidine (4%), granulating, drying and screening the dried granules: adding microcrystalline cellulose (8%), maize starch (8%), sodium glycollate (4%) and magnesium stearate (0.5%) to the granules and compressing into tablets containing 100 mg, 150 mg or 200 mg of the free base of the product of Example 2.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Dc Digital Transmission (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)
  • Luminescent Compositions (AREA)
  • Pyridine Compounds (AREA)
  • Lubricants (AREA)
  • Optical Filters (AREA)
  • Saccharide Compounds (AREA)

Claims (19)

1. Verfahren zur Herstellung einer Verbindung der Formel (I)
Figure imgb0069
oder eines pharmazeutisch verträglichen Salzes davon, wobei
R1 eine 2- oder 4-Imidazolylgruppe die gegebenenfalls durch C1-6-Alkyl, Halogen, Trifluormethyl oder Hydroxymethyl substituiert ist;
eine 2-Thiazolylgruppe;
eine 2-Guanidino-4-thiazolylgruppe, die gegebenenfalls durch Chlor, brom oder C1-6-Alkyl substitiuert ist;
eine 2-(5-Amino-1,3,4-thiadiazolylgruppe);
eine 3-Isothiazolylgruppe, die gegebenenfalls durch Chlor oder Brom substituiert ist;
eine 3-(1,2,5)-Thiadiazolylgruppe, die gegenenfalls durch Chlor oder Brom substituiert ist;
eine 2-Pyridylgruppe, die gegebenenfalls durch ein oder mehrere C1-6-Alkyl-, C1-6-Alkoxy-, Halogen-, Amino- oder Hydroxyeinheiten substituiert ist, oder in 4-Stellung durch einen Rest der Formel R3R4N(CH2)m― substituiert ist, wobei R3 und R4 unabhängig voneinander Wasserstoff, C1-s-Alkyl, Phenyl-(C1-6)-alkyl, Thienyl-(C1-s)-alkyl, Furyl-(C1-6)-alkyl, Hydroxy-(C1-6)-alkyl, Halogen-(C1-6)-alkyl oder C3-8-Cycloalkyl bedeuten, oder zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-8- gliedrigen gesättigten Ring bilden, und m einen Wert von 1 bis 6 aufweist;
eine 2-Furyl- oder 2-Thienylgruppe, die beide gegebenenfalls in 5-Stellung durch einen Rest der Formel R5R6N(CH2)m― substitiuert sein können, wobei R5 und R6 unabhängig voneinander Wasserstoffatome, C1-s-Alkyl, C3-8-Cycloalkyl, Halogen-(C1-6)-alkyl, C3-6-Alkenyl, Phenyl-(C1-6)-alkyl, C3-6-Alkinyl, Hydroxy-(C1-6)-alkyl, C1-3-Alkoxy-(C1-6)alkyl, Trifluor-(C1-s)-alkyl, Amino-(C1-s)-alkyl, C1-3-Alkylamino-(C1-6)-alkyl oder Di-(C1-3)-alkylamino-(C1-6)-alkyl bedeuten, oder R5 und R6 zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5 bis 8-gliedrigen gesättigten Ring bilden;
oder eine Phenylgruppe bedeutet, die gegebenenfalls durch C1-s-Alkyl, C1-6-Alkoxy, Hydroxy, Halogen, Trifluormethyl, Nitro, Amino, C1-6-Alkylamino, C1-6-Alkanoylamino, Di-(C1-s)-alkylamino oder Cyano substituiert ist, und ferner gegebenenfalls in einer der 3-, 4- oder 5-Stellungen durch Reste der Formeln ―(CH2)mNR5R6―OCH2CH2NR5R6 oder ―OCH2CH2CH2NR5R6 substituiert sein kann;
X eine Methylengruppe bedeutet, oder, wenn R1 eine gegebenenfalls substitiuerte Pyridyl- oder Phenylgruppe darstellt, X auch Sauerstoff sein kann;
Y Schwefel oder eine Methylengruppe bedeutet, mit der Maßgabe, daß mindestens einer der Reste X und Y eine Methylengruppe darstellt;
Z ein Wasserstoffatom oder einen C1-6-Alkylrest darstellt;
A eine C1-s-Methylengruppe oder eine Gruppe der Formel ―(CH2)pW(CH2)q bedeutet, wobei W Sauerstoff oder Schwefel ist und p und q derartige Werte besitzen, daß ihre Summe 1 bis 4 ist;
R2 eine Pyridon-Einheit bedeutet, die am Stickstoffatom durch einen Rest R7 substituiert ist, wobei R7 einen Rest der Formel ―(CH2)rNR8R9 bedeutet, wobei R8 und R9 unabhängig voneinander Wasserstoff, C1-6-Alkyl, C3-8-Cycloalkyl, C3-6-Alkenyl, Phenyl-C1-s-alkyl, C3-3-Alkinyl, Hydroxy-(C1-6)-alkyl, C1-3-Alkoxy-(C1-6)-alkyl, Trifluor-(C1-s)-alkyl, Amino-(C1-s)-alkyl, C1-3-Alkylamino-(C1-6)-alkyl oder Di-(C1-3)-alkyl- amino(C1-s)-alkyl darstellt, oder R8 und R9 zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen Pyrrolidino-, Piperidino- oder Hexahydroazepinoring bilden, und r 2 bis 6 ist; oder R7 einen C1-6-Alkyl-, C3-7-Cycloalkyl-(C1-6)-alkyl, Hydroxy-C2-6-alkyl-, C1-6-Alkoxy-C2-6-alkyl-, Phenyl-C1-6-alkoxy C2-6- alkyl-, Phenoxy-C2-6-alkyl- oder Phenyl-(C1-s)-alkylrest bedeutet, und die Pyridon-Einheit gegebenenfalls durch C1-4-Alkyl, C1-4-Alkoxy, Hydroxy, Halogen, Amino oder Phenoxy substituiert ist:
mit der Maßgabe, daß wenn X, Y und A alle eine Methylengruppe bedeuten, R einen C1-4-Alkylrest, gegebenenfalls durch Hydroxy, C1-4-Alkoxy oder Phenyl substituiert, bedeutet, und Z ein Wasserstoffatom darstellt, R1 keine 2-Pyridylgruppe bedeutet, die disubstituiert ist, in 3-Stellung durch Halogen, Amino, C1-4-Alkyl oder C3-4-Alkoxy und in 5-Stellung durch Halogen, Amino oder C1-4-Alkyl, umfassend:
a) die Umsetzung einer Verbindung der Formel (II) mit einer Verbindung der Formel (III)
Figure imgb0070
wobei R1, X, A, Y, Z und R2 wie vorstehend definiert sind und Q eine durch Amin verdrängbare Gruppe darstellt; oder
b) für Verbindungen der Formel (I), in denen X eine Methylengruppe bedeutet und Y Schwefel ist, Umsetzung einer Verbindung der Formel (IV)
Figure imgb0071
in der R1 wie vorstehend definiert ist, und L eine durch Thiol verdrängbare Gruppe darstellt, mit einer Verbinduna der Formel (V)
Figure imgb0072
in der A, Z und R2 wie vorstehend definiert sind; oder
c) Umsetzung einer Verbindung der Formel (VI)
Figure imgb0073
in der R1, X und Y wie vorstehend definiert sind, mit einer Verbindung der Formel (VII)
Figure imgb0074
in der Z, A und R2 wie vorstehend definiert sind und R17 einen C1-6-Alkylrest bedeutet; oder
d) für Verbindungen der Formel (I), in der R1 einen Substituenten der Formel R3R4N(CH2)m― oder R5R6N(CH2)m aufweist, Reduktion einer Verbindung der Formel (VIII)
Figure imgb0075
in der R2, A, Z, X und Y wie vorstehend definert sind, und R18 eine zu einem Rest R1 mit einem Substituenten der Formel R3R4N(CH2)m― oder R5R6N(CH2)m -reduzierbare Gruppe bedeutet; oder
e) Reduktion einer Verbindung der Formel (IX)
Figure imgb0076
in der R1, X, Y, Z und A wie vorstehend definiert sind und R19 eine Gruppe der Formel -CONH- oder -C=NH- darstellt; oder
f) zur Herstellung von Verbindungen, in denen R1 eine gegebenenfalls substituierte Phenylengruppe bedeutet und X ein Sauerstoffatom ist, Umsetzung einer Verbindung der Formel (X) oder ein chemisches Äquivalent davon mit einer Verbindung der Formel (XI)
Figure imgb0077
Figure imgb0078
in denen R1, Z, A und R2 wie vorstehend definiert sind und Q1 eine durch Phenol oder ein chemisches Äquivalent davon verdrängbare Einheit darstellt; oder
g) zur Herstellung von Verbindungen, in denen X eine Methylengruppe bedeutet und Y Schwefel ist, Umsetzung einer Verbindung der Formel (XII) mit einer Verbindung der Formel (XIII) oder einem chemischen Äquivalent davon
Figure imgb0079
Figure imgb0080
in denen R1, R2, A und Z wie vorstehend definiert sind und Q2 eine durch Thiol oder ein chemisches Äquivalent davon verdrängbare Gruppe darstellt;
und gegebenenfalls danach Herstellung eines pharmazeutisch verträglichen Salzes.
2. Verfahren nach Anspruch 1, wobei X eine Methylengruppe bedeutet, wenn R1 eine gegebenenfalls substituierte 2-Pyridylgruppe darstellt, wobei das Verfahren eine der Umsetzungen a) bis c) gemäß Anspruch 1 umfaßt.
3. Verfahren nach Anspruch 1, in der R1 die Unterformel (i) aufweist
Figure imgb0081
in der R14 und R15 unabhängig voneinander einen C1-6-Alkylrest bedeuten oder zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen Pyrrolidino; oder Piperidinoring bilden, und R16 eine 4-Pyrid-2-yl-, 5-Furan-2-yl- oder 1,3-Phenylengruppe darstellt.
4. Verfahren nach Anspruch 3, in der R16 eine 5-Furan-2-yl- oder 1,3-Phenylengruppe bedeutet.
5. Verfahren nach einem der Ansprüche 1 bis 4, in dem R7 eine Methyl-, Äthyl-, n-Butyl-, Benzyl- oder Dimethylaminoäthylgruppe bedeutet.
6. Verfahren nach den Ansprüchen 1 oder 2 zur Herstellung von
2-[2-(5-Methyl-4-imidazolylmethylthio)-äthylamino]-5-(1-methyl-2-oxopyridin-4-ylmethyl)-pyrimidin-4- on oder eines pharmazeutisch verträglichen Salzes davon,
2-[2-(2-Dimethylaminomethyl-5-furylmethylthio)-äthylamino]-5-(1-methyl-2-oxopyridin-4-ylmethyl)-pyrimidin-4-on oder eines pharmazeutisch verträglichen Salzes davon,
2-[2-(5-Methyl-4-imidazolylmethylthio)-äthylamino]-5-(1-n-butyl-2-oxopyridin-4-ylmethyl)-pyrimidin-4- on oder eines pharmazeutisch verträglichen Salzes davon,
2-[2-(2-Dimethylaminomethyl-5-furylmethylthio)-äthylamino]-5-(1-n-butyl-2-oxopyridin-4-ylmethyl)-pyrimidin-4-on oder eines pharmazeutisch verträglichen Salzes davon,
2-[2-(2-Guanidino-4-thiazolylmethylthio)-äthylamino]-5-(1-n-butyl-2-oxopyridin-4-ylmethyl)-pyrimidin-4-on oder eines pharmazeutisch verträglichen Salzes davon,
2-[2-(5-Methyl-4-imidazolylmethylthio)-äthylamino]-5-(1-benzyl-2-oxopyridin-4-ylmethyl)-pyrimidin-4- on oder eines pharmazeutisch verträglichen Salzes davon,
2-[2-(2-Dimethylaminomethyl-5-furylmethylthio)-äthylamino]-5-(1-benzyl-2-oxopyridin-4-ylmethyl)-pyrimidin-4-on oder eines pharmazeutisch verträglichen Salzes davon,
2-[2-(2-Dimethylaminomethyl-5-furylmethylthio)-äthylamino]-5-[1-(2-dimethylaminoäthyl)-2-oxopyridin-4-ylmethyl)-pyrimidin-4-on oder eines pharmazeutisch verträglichen Salzes davon,
2-[3-[3-(Piperidinomethyl)-phenoxy]-propylamino]-5-(1-n-butyl-2-oxopyridin-4-ylmethyl)-pyrimidin-4- on oder eines pharmazeutisch verträglichen Salzes davon,
2-[3-[3-(Piperidinomethyl)-phenoxy]-propylamino]-5-(1-methyl-2-oxopyridin-4-ylmethyl)-pyrimidin-4- on oder eines pharmazeutisch verträglichen Salzes davon,
2-[3-[4-(Piperidinomethyl-pyrid-2-yloxy]-propylamino]-5-(1-methyl-2-oxopyridin-4-ylmethyl)-pyrimidin-4-on oder eines pharmazeutisch verträglichen Salzes davon,
2-[2-[4-(Dimethylaminomethyl)-pyrid-2-ylmethylthio]-äthylamino]-5-(1-methyl-2-oxopyridin-4-ylmethyl)-pyrimidin-4-on oder eines pharmazeutisch verträglichen Salzes davon,
2-[2-(4-(Dimethylaminomethyl)-pyrid-2-ylmethylthio]-äthylamino]-5-(1-n-butyl-2-oxopyridin-4-ylmethyl)-pyrimidin-4-on oder eines pharmazeutisch verträglichen Salzes davon.
7. Verfahren zur Herstellung von 2 - [2 - (Dimethylaminomethyl - 5 - furan - 2 - ylmethylthio)-äthyl- amino] - 5 - (1-methyl - 2 - oxopyridin - 4 - ylmethyl) - pyridin - 4 - on, umfassend die Umsetzung von 2 - Nitroamino - 5 - (1 - methyl - 2 - oxopyridin - 4 - ylmethyl) - pyrimidin - 4 - on und 2 - (2 - Dimethylaminomethyl - 5 - furylmethylthio) - äthylamin.
8. Verfahren zur Herstellung von 2 - [3 - [4 - (Piperidinomethyl) - pyrid - 2 - -yloxy] - propylamino] - 5 - (1 - methyl - 2 - oxopyridin - 4 - ylmethyl) - pyrimidin - 4 - on, umfassend die Umsetzung von 2 - Nitroamino - 5 - (1 - methyl - 2 - oxopyridin - 4 - ylmethyl) - pyridin - 4 - on und 3 - [3 - (Piperidinomethyl) - phenoxy] - propylamin.
9. Verfahren zur Herstellung einer pharmazeutisch verträglichen Zusammensetzung, umfassend das Zusammenbringen einer Verbindung der Formel (I) gemäß Anspruch 1 und eines pharmazeutisch verträglichen Trägers.
10. Verfahren zur Herstellung einer Verbindung der Formel (III)
Figure imgb0082
in der Q eine Nitroamino-, C1-s-Alkylthio- oder Benzylthiogruppe darstellt und A, Z und R2 wie in Anspruch 1 definiert sind, umfassend:
a) für eine Verbindung der Formel (III) in der Q eine Nitroaminogruppe bedeutet, Umsetzung von Nitroguanidin und einer Verbindung der Formel (VII) gemäß Anspruch 1, oder
b) für eine Verbindung der Formel (III) in der Q eine C1-6-Alkylthio- oder Benzylthiogruppe bedeutet, Umsetzung einer Verbindung der Formel (VII) gemäß Anspruch 1 mit Thioharnstoff und anschließende Alkylierung oder Benzylierung.
EP83307257A 1982-12-03 1983-11-29 Aminopyrimidinone als Histamin-H2-Antagonisten Expired - Lifetime EP0117345B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT83307257T ATE50574T1 (de) 1982-12-03 1983-11-29 Aminopyrimidinone als histamin-h2-antagonisten.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8234615 1982-12-03
GB8234615 1982-12-03

Publications (3)

Publication Number Publication Date
EP0117345A2 EP0117345A2 (de) 1984-09-05
EP0117345A3 EP0117345A3 (en) 1985-09-11
EP0117345B1 true EP0117345B1 (de) 1990-02-28

Family

ID=10534737

Family Applications (1)

Application Number Title Priority Date Filing Date
EP83307257A Expired - Lifetime EP0117345B1 (de) 1982-12-03 1983-11-29 Aminopyrimidinone als Histamin-H2-Antagonisten

Country Status (18)

Country Link
US (1) US4540699A (de)
EP (1) EP0117345B1 (de)
JP (1) JPS59110692A (de)
KR (1) KR840006995A (de)
AT (1) ATE50574T1 (de)
AU (1) AU2175083A (de)
CA (1) CA1208215A (de)
DE (1) DE3381243D1 (de)
DK (1) DK552283A (de)
ES (1) ES527739A0 (de)
FI (1) FI834410A (de)
GR (1) GR79023B (de)
IL (1) IL70341A0 (de)
JO (1) JO1275B1 (de)
NO (1) NO834438L (de)
PT (1) PT77757B (de)
ZA (1) ZA838987B (de)
ZW (1) ZW26083A1 (de)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8421427D0 (en) * 1984-08-23 1984-09-26 Smith Kline French Lab Chemical compounds
DE3532880A1 (de) * 1985-09-14 1987-03-26 Basf Ag 1,4-disubstituierte pyrazolderivate
JPH0613486B2 (ja) * 1987-12-07 1994-02-23 株式会社池田模範堂 ピリミドン誘導体及びその医薬的に許容される塩
FR2686084B1 (fr) * 1992-01-10 1995-12-22 Bioprojet Soc Civ Nouveaux derives de l'imidazole, leur preparation et leurs applications therapeutiques.
USRE37303E1 (en) * 1992-01-10 2001-07-31 Institut National Del La Sante Et De La Recherche Medicale Imidazole compounds and their therapeutic applications
US20220242824A1 (en) * 2019-05-14 2022-08-04 Conopco, Inc., D/B/A Unilever Cosmetic composition
US11826453B2 (en) 2019-05-14 2023-11-28 Conopco, Inc. Hair care composition comprising piroctone olamine
WO2022034121A1 (en) 2020-08-11 2022-02-17 Université De Strasbourg H2 blockers targeting liver macrophages for the prevention and treatment of liver disease and cancer

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3980781A (en) * 1966-03-31 1976-09-14 Imperial Chemical Industries Limited Fungicidal composition and method containing 2-amino-pyrimidines
GB1419994A (en) * 1973-05-03 1976-01-07 Smith Kline French Lab Heterocyclicalkylaminotheterocyclic compounds methods for their preparation and compositions comprising them
EP0017680B1 (de) * 1979-04-11 1982-04-21 Smith Kline & French Laboratories Limited Pyrimidon-Derivate, Verfahren zu deren Herstellung und diese enthaltende pharmazeutische Zusammensetzungen

Also Published As

Publication number Publication date
DK552283A (da) 1984-06-04
GR79023B (de) 1984-10-02
PT77757A (en) 1983-12-01
ES8504792A1 (es) 1985-04-16
ES527739A0 (es) 1985-04-16
AU2175083A (en) 1984-06-07
ATE50574T1 (de) 1990-03-15
US4540699A (en) 1985-09-10
DE3381243D1 (de) 1990-04-05
NO834438L (no) 1984-06-04
CA1208215A (en) 1986-07-22
DK552283D0 (da) 1983-12-01
JO1275B1 (en) 1985-04-20
JPS59110692A (ja) 1984-06-26
PT77757B (en) 1986-04-16
EP0117345A3 (en) 1985-09-11
ZW26083A1 (en) 1985-04-17
ZA838987B (en) 1985-02-27
FI834410A0 (fi) 1983-12-01
KR840006995A (ko) 1984-12-04
FI834410A (fi) 1984-06-04
IL70341A0 (en) 1984-02-29
EP0117345A2 (de) 1984-09-05

Similar Documents

Publication Publication Date Title
EP0050458B1 (de) 2-Guanidino-4-heteroarylthiazole und diese enthaltende Arzneimittel
EP0068834B1 (de) Pyrimidinonderivate und diese enthaltende pharmazeutische Zusammenstellungen
EP0117345B1 (de) Aminopyrimidinone als Histamin-H2-Antagonisten
AU702609B2 (en) Pyridylthio compounds for controlling helicobacter bacteria
US4377576A (en) 5-(Heterocyclic amino-propionyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-ones
US4694008A (en) Chemical compounds
EP0051371B1 (de) Therapeutische Zusammenstellungen von Imidazol-Pyridinen
EP0134096B1 (de) Aminopyrimidinon-Derivate als Histamin-H2-Antagonisten
EP0039989B1 (de) Pyrimidonderivate, Verfahren zu ihrer Herstellung und sie enthaltende pharmazeutische Zubereitungen
US4935424A (en) 4 or 5-(substituted piperazinylalkyl)-2-aminothiazoles as antipsychotic agents
US4567176A (en) 4H-Imidazol-4-ones and their pharmaceutical use
US4738969A (en) Substituted aminopyridones and aminoquinolones having histamine H2 -receptor blocking activity
JPS6330903B2 (de)
US4808589A (en) Pyrimidone derivatives
US3378564A (en) Certain pyridyl tetrazole derivatives
US4468399A (en) 2-[2-(2-Aminoalkyl-4-thiazolylmethylthio)alkyl]-amino-5-substituted-4-pyrimidones
CA1206151A (en) Pyrimidone anti-ulcer agents
EP0081955B1 (de) Benzo-Kondensierte heterocyclische Derivate
US4571398A (en) Cytosine derivatives having histamine H2 -antagonist activity
CA1166253A (en) 4-amino-6-(pyridinyl)-3(2h)-pyridazinones, preparation and cardiotonic use
EP0172968A1 (de) Aminothiadiazinderivate als Histamin-H2-Antagonisten
JPS5936674A (ja) Ｎ−置換グアニジノチアゾ−ル誘導体およびその製造法
KR820001993B1 (ko) 히스타민h₂수용체 길항작용을 가진 니트로 화합물의 제조방법
EP0206623B1 (de) Pyridinderivate
GB2137197A (en) Thicro-thiazole h2 antagonists

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19831205

AK Designated contracting states

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

AK Designated contracting states

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

17Q First examination report despatched

Effective date: 19880628

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Effective date: 19900228

Ref country code: LI

Effective date: 19900228

Ref country code: CH

Effective date: 19900228

Ref country code: AT

Effective date: 19900228

REF Corresponds to:

Ref document number: 50574

Country of ref document: AT

Date of ref document: 19900315

Kind code of ref document: T

ITF It: translation for a ep patent filed
REF Corresponds to:

Ref document number: 3381243

Country of ref document: DE

Date of ref document: 19900405

ET Fr: translation filed
REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Effective date: 19901129

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19901130

Ref country code: BE

Effective date: 19901130

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed
BERE Be: lapsed

Owner name: SMITH KLINE & FRENCH LABORATORIES LTD

Effective date: 19901130

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Effective date: 19910601

NLV4 Nl: lapsed or anulled due to non-payment of the annual fee
GBPC Gb: european patent ceased through non-payment of renewal fee
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Effective date: 19910731

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Effective date: 19910801

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST